INSERM, UMRS 970, Paris Cardiovascular Research Center, Paris, France.
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Nat Genet. 2018 Mar;50(3):355-361. doi: 10.1038/s41588-018-0053-8. Epub 2018 Feb 5.
Primary aldosteronism is the most common and curable form of secondary arterial hypertension. We performed whole-exome sequencing in patients with early-onset primary aldosteronism and identified a de novo heterozygous c.71G>A/p.Gly24Asp mutation in the CLCN2 gene, encoding the voltage-gated ClC-2 chloride channel , in a patient diagnosed at 9 years of age. Patch-clamp analysis of glomerulosa cells of mouse adrenal gland slices showed hyperpolarization-activated Cl currents that were abolished in Clcn2 mice. The p.Gly24Asp variant, located in a well-conserved 'inactivation domain', abolished the voltage- and time-dependent gating of ClC-2 and strongly increased Cl conductance at resting potentials. Expression of ClC-2 in adrenocortical cells increased expression of aldosterone synthase and aldosterone production. Our data indicate that CLCN2 mutations cause primary aldosteronism. They highlight the important role of chloride in aldosterone biosynthesis and identify ClC-2 as the foremost chloride conductor of resting glomerulosa cells.
原醛症是最常见和可治愈的继发性高血压形式。我们对早发性原醛症患者进行了全外显子组测序，在一名 9 岁确诊的患者中发现 CLCN2 基因的 c.71G>A/p.Gly24Asp 杂合新生突变，该基因编码电压门控 ClC-2 氯离子通道。对小鼠肾上腺切片的球状带细胞进行膜片钳分析显示，超极化激活 Cl 电流在 Clcn2 小鼠中被消除。该 p.Gly24Asp 变异位于一个高度保守的“失活域”，消除了 ClC-2 的电压和时间依赖性门控，并在静息电位下强烈增加 Cl 电导。ClC-2 在肾上腺皮质细胞中的表达增加了醛固酮合酶的表达和醛固酮的产生。我们的数据表明 CLCN2 突变导致原醛症。它们突出了氯离子在醛固酮生物合成中的重要作用，并确定 ClC-2 为静息状带细胞的首要氯离子导体。
